Encapsulated drug compositions and methods of use thereof

ABSTRACT

Various aspects of the present disclosure provide compositions, coatings and implantable devices including a drug and an excipient. In certain embodiments the excipient and the drug are present at a weight ratio of between 10 to 1 and 1 to 10 drug to excipient. In certain other embodiments, the excipient and the drug form particles in which the drug is encapsulated by the excipient. Other aspects of the disclosure provide methods of manufacturing and using such compositions, coatings and implantable devices.

RELATED APPLICATIONS

This patent application is a continuation of U.S. patent applicationSer. No. 14/454,345, filed Aug. 7, 2014, the entire contents of whichapplication is hereby incorporated by reference.

TECHNICAL FIELD

The present disclosure generally relates to compositions including adrug encapsulated by an excipient, to devices including suchcompositions and to methods of preparing and using such compositions anddevices.

BACKGROUND

Local delivery of a therapeutic agent can be useful in the treatment ofmany medical conditions. Illustratively, local delivery of a therapeuticagent within a body vessel or to a selected portion of internal bodytissue can eliminate or reduce the need for systemic delivery of thetherapeutic agent thus minimizing any potential adverse effect of thetherapeutic agent on areas of the body not needing treatment.

Minimally invasive implantable medical devices, such as balloons,catheters and stents, can provide a platform for delivering therapeuticagents to internal body tissue. For example, balloon catheters or stentsmay be used to deliver a therapeutic agent directly to the target sitewithin a body vessel such as an artery or vein.

One example of a condition that can be beneficially treated by localadministration of a therapeutic agent with a balloon catheter is thedelivery of a therapeutic agent in combination with percutaneoustransluminal coronary angioplasty (PTCA), a technique used to dilatestenotic portions of blood vessels. Although PTCA and related proceduresaid in alleviating intraluminal constrictions, such constrictions orblockages may reoccur in many cases. The cause of these recurringobstructions, termed restenosis, may be due to the body responding tothe surgical procedure. Restenosis of the vessel may develop overseveral months after the procedure, and may require another angioplastyprocedure or a surgical bypass operation to correct. Proliferation andmigration of smooth muscle cells (SMC) from the media layer of the lumento the intimal layer cause an excessive production of extracellularmatrices (ECM), which is believed to be one of the leading contributorsto the development of restenosis. The extensive thickening of tissuesnarrows the lumen of the blood vessel, constricting or blocking theblood flow through the vessel.

Drugs that inhibit restenosis may be locally delivered during PTCA froma catheter or by placement of a stent configured to continue to releasethe drug after the PTCA procedure. The delivery of the drug fromcoatings in these and other minimally invasive procedures can becomplicated by the need both to have a coating that is durable duringdelivery, but which effectively delivers the drug when implanted in theregion where local treatment is desired. Because natural biologicalenvironments are aqueous, it can occur that a coating containing awater-insoluble drug is sufficiently durable during travel to theintended delivery site, but then fails to optimally deliver the drug atthe site. Needs thus exist for compositions, coatings, and coatedimplantable medical devices which enable the beneficial delivery of adrug locally to a site intended for treatment.

SUMMARY

One aspect of the present invention relates to a medical deviceincluding a base structure having a surface and a coating containing adrug and an excipient on the surface. In certain embodiments, the drugand excipient are present at a weight ratio of between 10:1 and 1:10drug to excipient. In other embodiments, the excipient can be aterpeniod, for example a carotenoid, a phenolic compound including apolyphenol, a isoflavonoid, a curcuminoid, and a flavonoid which includeflavones, flavonols, flavanones, and isoflavones. Specific examplesinclude Chrysin, Tutin, Naringenin, and flavan-3-ols which can begallate containing compounds like epigallocatechin gallate or compoundscomprised of two or more flavan-3-ol units such as tannins, for exampletannic acid.

In some embodiments, the coating includes a plurality of particlescontaining the drug encapsulated by the excipient. In other embodiments,the excipient is a gallate containing compound, epi gallo catechingallate, epi catechin gallate or tannic acid. In yet other embodiments,the coating consists essentially of the excipient and the drug. Forexample, the coating can be free of a polymer or non-polymer carriermatrix.

In some embodiments, the drug is an immunosuppressive agent, anantiproliferative agent, a microtubule stabilizing agent, arestenosis-inhibiting agent or an inhibitor of the mammalian target ofrapamycin. In other embodiments, the drug is a taxane compound, forexample paclitaxel. The paclitaxel can be present in a crystalline form,for example dihydrate paclitaxel. The medical device can include anexpandable device, for example a balloon or an expandable stent

Another aspect of the present invention generally relates to a methodfor delivering a drug locally to tissue of a patient. In one embodiment,the method includes contacting a vessel wall of the patient with anembodiment of the medical device described herein. The device ismaintained in contact with the vessel wall for a time sufficient todeliver the drug to the tissue of the patient.

Yet another aspect provides a method for treating a patient sufferingfrom a disease or condition. In one embodiment, the method includesimplanting a medical device as described herein in the patient andmaintaining the implantable medical device within the patient for a timesufficient to deliver a therapeutically effective amount of the drug toa tissue of the patient. In various embodiments, the implantable medicaldevice is a stent, a vascular stent, a ureteral stent, a catheter, aballoon, a balloon catheter, a stent graft, a wire guide or a cannula.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 provides a perspective view of a drug-delivering balloon catheterin accordance with one embodiment of the invention in an inflatedcondition.

FIG. 2 provides a cross-sectional view of the balloon-mounted region ofthe balloon catheter of FIG. 1 taken along a central longitudinal axis.

FIG. 3 provides a cross-sectional view of the catheter shaft of theballoon catheter of FIG. 1 taken along line 3-3 and viewed in thedirection of the arrows.

FIG. 4 provides a perspective view of the balloon catheter of FIG. 1 ina folded condition.

FIG. 5 provides a cross-sectional view of the balloon catheter of FIG. 4taken along line 5-5 and viewed in the direction of the arrows.

FIG. 5a provides a cross-sectional view illustrating an alternatecoating pattern to that shown in FIG. 5.

FIG. 5b provides a cross-sectional view illustrating another alternatecoating pattern to that shown in FIG. 5.

FIG. 6 provides a cross-sectional view of the balloon catheter of FIG. 1taken along a longitudinal axis and illustrating an alternate coatingconfiguration.

FIG. 7 provides a cross-sectional view of the balloon catheter of FIG. 1taken along a longitudinal axis and illustrating another alternatecoating configuration.

FIG. 8 provides a perspective view of a therapeutic agent-deliveringstent in accordance with one embodiment of the invention.

FIG. 9 provides a perspective view of a coated drug-delivering ballooncatheter having a coated balloon-expandable stent mounted thereon inaccordance with an embodiment of the invention.

FIG. 10 provides a side view of a drug-delivering scoring ballooncatheter in accordance with one embodiment of the invention in aninflated condition.

FIG. 11 provides an enlarged cross-sectional view of a dilation elementof the scoring balloon catheter of FIG. 10 and adjacent balloon wallfilm portions.

FIG. 12 is a graph showing flow loop results. The bars show the tissueuptake of drug as a percentage of the initial drug on the balloon.

FIG. 13 is a graph showing the effect of tannic acid on the durabilityof a paclitaxel drug coating.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

For the purpose of promoting an understanding of the principles of theinvention, reference will now be made to embodiments, some of which areillustrated in the drawings, and specific language will be used todescribe the same. It will nevertheless be understood that no limitationof the scope of the invention is thereby intended. Any alterations andfurther modifications in the described embodiments, and any furtherapplications of the principles of the invention as described herein arecontemplated as would normally occur to one skilled in the art to whichthe invention relates.

In the discussions that follow, a number of potential features orselections of the drug, excipient, implantable medical device structure,or other aspects, are disclosed. It is to be understood that each suchdisclosed feature or features can be combined with the generalizedfeatures discussed herein, to form a disclosed embodiment of the presentinvention.

Definitions

The term “therapeutic effect” as used herein means an effect whichinduces, ameliorates or otherwise causes an improvement in thepathological symptoms, disease progression or physiological conditionsassociated with or resistance to succumbing to a disorder, for examplerestenosis, of a human or veterinary patient. The term “therapeuticallyeffective amount” as used with respect to a drug means an amount of thedrug which imparts a therapeutic effect to the human or veterinarypatient.

The term “water-insoluble” as applied to a drug herein refers to atherapeutic agent having a solubility in water at 25° C. of less than 2milligrams per milliliter (mg/ml). More preferably, the water-insolubledrug has a solubility in water at 25° C. of less than 1 mg/ml, even morepreferably less than 0.1 mg/ml, and in certain embodiments less than 10micrograms per milliliter (μg/ml).

Compositions

One aspect of the present disclosure relates to compositions includingat least one drug and at least one excipient. In certain embodiments,the drug and the excipient are present at a weight ratio of between 10to 1 and 1 to 10 drug to excipient. In other embodiments, the drug andexcipient are present at a weight ratio of between 1 to 2 and 1 to 5 orbetween 1 to 1 and 1 to 5 drug to excipient. In yet other embodimentsthe drug and the excipient are present at a weight ratio such that theexcipient encapsulates the drug to form microparticles of encapsulateddrug.

The excipient can be a gallate containing compound such as, but notlimited to, epi gallo catechin gallate (EGCG) or tannic acid. In otherembodiments the excipient is a terpeniod, for example a carotenoid, aphenolic compound including polyphenols, isoflavonoids, curcuminoids,and flavonoids which include flavones, flavonols, flavanones, andisoflavones. Specific examples include Chrysin, Tutin, Naringenin, andflavan-3-ols which can be gallate containing compounds likeepigallocatechin gallate or compounds comprised of two or moreflavan-3-ol units such as tannins, for example tannic acid.

Yet other preferred compounds include compounds that contain thechemical moieties of gallate, catechin, tannin, catechol, or similarpolyphenol moieties, including naturally derived compounds, as well aspolymers that have been synthetically modified and covalently attachedto these moieties.

Drugs within the scope of the present embodiments includeantiproliferative agents immunosuppressive agents, restenosis-inhibitingagents, anti-cancer agents, analgesics/antipyretics, anesthetics,antiasthmatics, antibiotics, antidepressants, antidiabetics, antifungalagents, antihypertensive agents, anti-inflammatories, antineoplastics,antianxiety agents, sedatives/hypnotics, antianginal agents, nitrates,antipsychotic agents, antimanic agents, antiarrhythmics, antiarthriticagents, antigout agents, thrombolytic agents, hemorheologic agents,anticonvulsants, antihistamines, agents useful for calcium regulation,antibacterial agents, antiviral agents, antimicrobials, anti-infectives,bronchodilators, steroids and hormones.

Non-limiting examples of such drugs include doxorubicin, camptothecin,etoposide, mitoxantrone, cyclosporine, epothilones, napthoquinones, 5fluorouracil, methotrexate, colchicines, vincristine, vinblastine,gemcitabine, statins (for example atorvastatin, fluvastatin, lovastatin,pitavastatin, pravastatin, rosuvastatin and simvastatin), steroids (forexample cortisteroids, prednisilone and dexamethazone) mitomycin andderivatives or analogues of these agents.

Preferred drugs include water-insoluble drugs including water-insolubleantiproliferative agents, immunosuppressive agents andrestenosis-inhibiting agents. In particular embodimentsantiproliferative agents or immunosuppressive agents that arerestenosis-inhibiting agents are utilized, which can be effective toinhibit restenosis of a vessel when applied to the inner wall of thevessel. In this regard, “restenosis-inhibiting” includes preventing orreducing the extent of restenosis. The inhibition of restenosis may beobserved after a procedure in which the vessel wall is injured due todilatation, for example during dilatation with a balloon of a ballooncatheter and/or by expansion of a stent.

The water-insoluble restenosis-inhibiting agent may be a microtubulestabilizing agent such as paclitaxel, a paclitaxel analog, or apaclitaxel derivative or other taxane compound; a macrolideimmunosuppressive agent such as sirolimus (rapamycin), pimecrolimus,tacrolimus, everolimus, zotarolimus, novolimus, myolimus, temsirolimus,deforolimus, or biolimus; an antiproliferative agent; a smooth musclecell inhibitor; an inhibitor of the mammalian target of rapamycin (mTORinhibitor); or a mixture of two, or two or more of any of these. Theseor other water-insoluble restenosis-inhibiting agents, including eachagent or agent type identified herein, more preferably have a solubilityin water at 25° C. of less than 1 mg/ml, even more preferably less than0.1 mg/ml, and in certain embodiments less than 10 micrograms/ml.Paclitaxel, sirolimus, pimecrolimus, tacrolimus, everolimus,zotarolimus, novolimus, myolimus, temsirolimus, deforolimus, andbiolimus are preferred water-insoluble restenosis-inhibiting agents foruse herein (each known to have a water solubility of less than about 10micrograms/ml).

In certain embodiments, the drug can be present in more than onepolymorphic form. For example, the drug can be a taxane agent includingone or more types of taxane agent(s). Taxane agent molecules having thesame molecular structure may be arranged in different solid forms.Taxane agent molecules can exist in solvated or non-solvated solid formsthat can be characterized and differentiated by one or more physicalproperties.

Typically, taxane agents in a solvated solid form dissolve more slowlyin an aqueous environment, for example in blood, than non-solvated solidforms, but are less durable than the non-solvated solid forms. Oncedissolved, the taxane agent molecules having identical molecularstructures but originating from different solid forms areindistinguishable in solution.

In one embodiment, the taxane agent is paclitaxel. Solid forms ofpaclitaxel at room temperature include: amorphous paclitaxel (“aPTX”),dihydrate crystalline paclitaxel (“dPTX”) and anhydrous crystallinepaclitaxel. These different solid forms of paclitaxel can becharacterized and identified using various solid-state analytical tools,for example as described by Jeong Hoon Lee et al., “Preparation andCharacterization of Solvent Induced Dihydrate, Anhydrous and AmorphousPaclitaxel,” Bull. Korean Chem. Soc. v. 22, no. 8, pp. 925-928 (2001),or in U.S. Pat. No. 8,642,063, issued Feb. 4, 2104, incorporated hereinby reference. For example, amorphous and dihydrate taxane solid formsmay be readily identified and differentiated by visual appearance andelution rates. The dihydrate taxane solid form typically has an opaquewhite color, while the amorphous dihydrate taxane solid form typicallyhas a clear transparent appearance.

In one embodiment, the drug is paclitaxel, including a crystalline(dihydrate) form of paclitaxel. The paclitaxel can be encapsulated toform microparticles including dihydrate paclitaxel encapsulated bycoating of excipient. In certain embodiments, the excipient is EGCG ortannic acid or a combination thereof.

The compositions of the present invention include those that may beadministered by oral, parenteral (e.g., intramuscular, intraperitoneal,intravenous, ICV, transcatheter arterial chemoembolization,intracisternal injection or infusion, subcutaneous injection, orimplant), by inhalation spray, nasal, vaginal, rectal, sublingual, ortopical routes of administration and may be formulated, alone ortogether, in suitable dosage unit formulations containing conventionalnon-toxic pharmaceutically acceptable carriers, adjuvants and vehiclesappropriate for each route of administration.

Coated Medical Devices

Other aspects of the present invention relate to medical devicesincorporating a releasable component including a particulate coatingincluding at least one drug encapsulated by an excipient. The excipientcan be one of those compounds disclosed above for example, a gallatecontaining compound such as, but not limited to, EGCG or tannic acid. Incertain embodiments, the medical devices are coated with or otherwisecontain the excipients or compositions as disclosed above.

The medical device may be any of a wide variety of devices having animplantable medical device structure sized and shaped for temporary orpermanent implantation in a human or veterinary patient. Medical deviceshaving structures implantable in a bodily passage will often be used.The bodily passage may for example be a passage of the alimentarysystem, the urogenital system, the biliary system, or the cardiovascularsystem. Medical devices including a device structure implantable in thecardiovascular system are preferred, including for example thoseimplantable in a vessel or chamber of the cardiovascular system of ahuman or animal patient through which blood travels. The passage may forexample be a tubular passage such as an artery or vein, or may be alarger chamber such as a ventricle or atrium of the heart. Implantablemedical devices that include structures that span or bridge betweencardiovascular or other bodily passages are also contemplated. Theimplantable medical device can be adapted to be entirely or onlypartially implanted in a cardiovascular passage or other bodily passage.

The releasable component may be incorporated into the structure of themedical device and/or be present in a coating on one or more surfaces ofthe device. The releasable component may also be provided in the form ofa fluid reagent for delivery by the device.

By way of example, the medical device can be or include a catheter, awire guide, a stent, a coil, a needle, a graft, a filter, a balloon, acutting balloon, a scoring balloon, a weeping (perfusion) balloon, orany combination of these. Suitable filters include for example vena cavafilters such as the Cook CELECT® and Cook Günther TULIP® and CookGianturco-Roehm Bird's NEST® filters available from Cook Medical,Bloomington Indiana, USA. Suitable stents include those without acovering, for example the Cook ZILVER® Cook ZILVER®-PTX stents availablefrom Cook Medical. Suitable stents also include those with a sheathcovering. Suitable coils include embolization coils. Suitable wireguides include for instance traditional wire guides as well as wireguides with an attached expandable structure for expansion within ablood vessel lumen, such as a coil, where the expandable structure canoptionally carry the coating or coatings as disclosed herein. These orother implants, in certain preferred embodiments, have at least aportion that is configured to expand during deployment so as to contactwalls of the passage in which they are implanted to anchor within thepassage. In this regard, both self-expanding and force-expandable (e.g.balloon-expandable) stents or other implantable medical devices arecontemplated as being within the scope of embodiments of the presentinvention.

The implantable medical device can be made from any suitable material orcombination of materials. Illustratively, the implantable medical devicecan include a metal such as stainless steel, tantalum, titanium,nitinol, cobalt, chromium, nickel, molybdenum, manganese, gold,platinum, inconel, iridium, silver, tungsten, elgiloy, alloys of any ofthese, or another biocompatible metal; carbon or carbon fiber; acalcium-containing inorganic material such as a ceramic; a materialcomposed of ceramic and metallic components (cermet); or a polymericmaterial. The material of construction for the implantable medicaldevice structure can be biodegradable or non-biodegradable.Nonbiodegradable polymers that can be used include, for example,cellulose acetate, cellulose nitrate, silicone, polyethyleneterephthalate, polyurethane, polyamide, polyester (e.g. Nylon),polyorthoester, polyanhydride, polyether sulfone, polycarbonate,polypropylene, high molecular weight polyethylene, andpolytetrafluoroethylene, or mixtures of these. Biodegradable polymersthat can be used include, for example, polylactic acid (PLA),polyglycolic acid (PGA), poly(lactic-co-glycolic acid) (PLGA),polyanhydride, polycaprolactone, polyhydroxybutyrate valerate, ormixtures of these. Biodegradable metals may also be used, including forexample a biodegradable magnesium alloy.

In some preferred embodiments herein, the implantable medical devicewill be or include a balloon catheter, such as an angioplasty ballooncatheter, a weeping or infusion balloon, a scoring balloon catheter or acutting balloon catheter. Such a balloon catheter can include at leastone balloon mounted on a catheter shaft, with the catheter shaftdefining an inflation lumen fluidly communicating with an interior ofthe balloon. The catheter shaft can also define a guide member lumen,for receiving an elongate guidewire or other guiding member for thecatheter. The guide member lumen can extend from a distal opening distalto the balloon to a proximal opening proximal to the balloon. Theproximal guide member lumen opening can occur in a sidewall of thecatheter shaft in a region proximate to the balloon (e.g. within about10 cm proximal to the proximal end of the balloon) and which ispositioned to reside within the patient during use of the ballooncatheter, as occurs for example in “rapid-exchange” balloon catheterconstructions, or can occur on the catheter shaft in a region positionedto reside external of the patient during use of the balloon catheter, asoccurs for example in so-called “over-the-wire” balloon catheterconstructions. The balloon catheter may include multiple balloons,usually in this case only two balloons, mounted in positions spacedlongitudinally from one another on the catheter shaft. In such cases theballoons may share a common inflation lumen defined by the cathetershaft, or each may have a separate inflation lumen defined by thecatheter shaft. In such balloon catheters having only two, or two ormore balloons, the distal opening of the guide member lumen can occurdistally of the distal-most balloon, and the proximal opening of theguide member lumen can occur proximal of the proximal-most balloon, ineither rapid-exchange or over-the-wire type configurations as discussedabove.

The balloon(s) of the balloon catheters herein may be configured forvascular angioplasty, and/or may have a balloon wall made of anysuitable balloon wall material, typically a polymeric balloon wallmaterial. The polymeric or other balloon wall material can beelastomeric, as in the case of an illustrative silicone elastomer, latexrubber elastomer, nylon elastomer, or polyurethane elastomer balloonfilm, where the balloon can expand upon inflation due to the expansionand thinning of the balloon wall material. The compliance of the balloonwall material in such elastomeric balloon applications is typicallygreater than 20% and more typically greater than 50%, and/or the burstpressure of such elastomeric balloons will typically be in the range ofabout 1.1 to about 2 atmospheres. In other embodiments, the polymeric orother balloon wall material can be inelastic, as in the case of anon-compliant or semi-compliant balloon (e.g. as commonly used inangioplasty and/or stent delivery balloons), where the balloon canexpand upon inflation due to the unfolding of the balloon wall materialfrom an initial folded configuration. Preferred balloon wall materialsfor non-compliant or semi-compliant balloons include polyamide (e.g. asin Nylon balloons), polyethylene terephthalate (PET), or polyurethanepolymers. At least a portion of and potentially the entirety of such anelongate, generally cylindrical outer surface can carry the drug andexcipient as discussed herein, either as the sole coating carried by thegenerally cylindrical outer surface or in combination with one or moreadditional coatings carried by the generally cylindrical outer surface.

In other preferred embodiments herein, the implantable medical devicewill be or include a stent. Such a stent may for example be aforce-expandable stent, such as a balloon-expandable stent, or aself-expanding stent. The stent may be made from any one of numerousmetals and alloys, including those identified hereinabove. The structureof the stent may be formed in a variety of ways to provide a suitableintraluminal support structure having an outer surface for contact withthe vessel wall upon implantation and an inner surface that faces thelumen of the vessel and that can be generally opposite the outersurface. For example, the stent may be made from a woven wire structure,a laser-cut cannula, individual interconnected rings, or another patternor design. In these or other constructions, the stent can include aplurality of struts each having an outer surface for contact with thevessel wall and an inner surface for facing the lumen of the vessel.

Such stents may be force-expandable, such as balloon-expandable, orself-expanding, as discussed above. Self-expanding stents of this typecan be made of a resilient metal, preferably a superelastic metal alloysuch as a superelastic nickel-titanium (Ni—Ti) alloy, as occurs forexample in the ZILVER® nitinol stent commercially available from CookMedical.

Any stent discussed above or elsewhere herein can have a stent surfacecarrying the releasable component as discussed herein, either as thesole coating carried by the stent surface, or in combination with one ormore additional coatings positioned underneath and/or overtop the layercontaining the releasable component. As well, surfaces of the stent notcarrying the releasable component may optionally be bare (uncoated), ormay carry one or more different coatings. Additionally, where the stentis mounted on a balloon of a balloon catheter for delivery, the surfaceof the balloon may carry the releasable component and potentially otherlayer(s) as described herein, and/or the surface of the stent may carrythe releasable component and potentially other layer(s) as describedherein. The practice of these and other variants will be within thepurview of those of ordinary skill in the art in view of the teachingsherein.

When the compositions are present in a coating on a surface of thedevice, the composition may constitute greater than 50, 75, 90, 95 or 99percentage by weight of the coating. In certain embodiments, thecoatings include less than about 5, 2, 1, 0.5, 0.1, 0.05 or 0.01percentage by weight of materials other than the drug and the excipient.In other embodiments, the coatings include less than about 5, 2, 1, 0.5,0.1, 0.05 or 0.01 percentage by weight of materials, such as polymers orother non-polymer carriers, that alter the release rate of the drug fromthe device when implanted.

Preferred drugs used in conjunction with implantable medical devicesinclude water-insoluble antiproliferative agents, immunosuppressiveagents, and restenosis-inhibiting agents. Particularly preferred arewater-insoluble restenosis-inhibiting agents, such as those describedabove. In certain preferred embodiments, paclitaxel is the only drugincluded in combination with the device.

The drug can be incorporated in the device at any suitable level.Typically, when coated onto a device such as a stent or a balloon, thedrug will be incorporated at a level of about 0.1 to about 1000micrograms per mm², or about 0.1 to about 100 micrograms per mm², and incertain preferred forms about 0.1 to about 10 micrograms per mm² orabout 0.5 to about 2 micrograms per mm² of the coated surface. Where twoor more drugs are included in the coating, the above-recited levels canapply to the combined weight of all the drug(s), or to the drug(s)individually. It will also be understood that the coating may containvariations in the level of drug in different regions of the coatingeither due to manufacturing variances or intentional design criteria.Thus, the present invention contemplates coatings in which the level ofdrug(s) is substantially uniform over the entire area covered by thecoating, or in which the level of drug(s) differs substantially in onearea of the coating as compared to another area covered by another areaof the coating. In certain preferred embodiments, paclitaxel isincorporated at a level in the range of 1 microgram per mm² to 10micrograms per mm², or in the range of 2 micrograms per mm² to 6micrograms per mm², or in the range of 0.5 micrograms per mm² to 2micrograms per mm² either as the only drug in the coating or incombination with one or more additional drugs In particularly beneficialimplantable medical devices of the invention, such paclitaxel-containingcoatings are carried on a surface of a stent, including for example anystent described herein, and/or on a surface of a balloon of a ballooncatheter, including for example any balloon catheter described herein.

The drug will typically be incorporated in the device in atherapeutically effective amount. In this regard, it will be understoodthat where the drug is a restenosis-inhibiting agent, therestonosis-inhibiting agent will be incorporated in the coating in anamount that is effective to inhibit restenosis when the implantablemedical device (e.g. a balloon or stent) is deployed so as to deliverthe drug from the implantable medical device to a wall of the artery,vein or other vessel or passage that is being treated by the device. Aswill be recognized, the level of a drug that will be therapeuticallyeffective will vary in accordance with the particular drug in use, theimplantable medical device in use, the implant site, the condition to betreated, the composition of the coating including the drug, and otherpotential factors. Through routine experimentation in view of thedisclosures herein the achievement of a therapeutically effective amountof drug will be within the purview of those of ordinary skilled in thefield.

The excipient can be included in the device in an amount effective toincrease the rate of release of the drug from the device at a site ofimplant of the implantable medical device structure. This capacity canbe demonstrated in, for example, in vivo testing, or in vitro testingwhere the level of the excipient are observed to increase the rate ofrelease of the drug(s) in water, or in an aqueous medium such as bloodserum or a 0.2 weight % aqueous solution of Heptakis(2,6-O-methyl)-beta-cyclodextrin (HCD), under static conditions at atemperature of 37° C.

In embodiments in which the releasable component is contained within orin a layer coating the implantable medical device, the excipientobserved to increase the amount of drug released when implanted, by 10,20, 30, 40, 50 75, 100, 125, 150, 200, 300 or 400 percentage as comparedto a device that is identical except for the absence of the excipient.

In certain other embodiments, the excipient is observed to increase thedelivery of the drug across a vessel wall and into the tissue of thepatient. The increase in the amount of the drug delivered to the tissueof the patient from a device including the excipient may depend upon anumber of factors, such as the nature of the vessel in which thecomposition is placed or device is implanted, as well as the environmentwithin the vessel and the construction of the implantable device.

However, the increase in the amount drug delivered through a vessel wallmay be characterized in an ex vivo assay in which the implantable deviceis placed in a section of the appropriate vessel and incubated in abuffer solution for a fixed time. In one such assay, a device, forexample, is placed in a section of porcine ureter, which is hydrated ina Phosphate Buffered Saline buffer. The ureter is incubated in a closedcontainer for a fixed time, for example 5 minutes at 37 deg. C. Afterthe incubation period, the drug present in the ureter tissue isextracted using an extraction solution, such as an enzyme solution,organic solvent, organic/aqueous mixture, or acidified mixture. Theextraction solution used is dependent on the drug being extracted. Theamount of drug present in the ureter and in the device is determinedusing, for example, an appropriate HPLC method.

In certain embodiments, the claimed devices include excipient sufficientto increase the amount of drug delivered, as measured by this assay, byat least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 70%, 100%, 150% or 200%compared to the amount of drug delivered, under the same conditions,from an otherwise identical device that does not include the excipient.In other embodiments, the devices include excipient sufficient toincrease the amount of drug delivered, as measured by this assay, withina period of 1, 5, 15, 30, 60, 120, 300, 500 or 1000 minutes by at least5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 70%, 100%, 150% or 200%. In yetother embodiments, the claimed devices include an amount of excipientsufficient to increase the amount of drug delivered, as measured by thisassay, within a period of 1, 5, 15, 30, 60 or 120 days by at least 5%,10%, 15%, 20%, 25%, 30%, 40%, 50%, 70%, 100%, 150% or 200%.

In certain embodiments, the excipient is effective to deliver atherapeutically effective amount of the drug to patient tissue in a timeperiod of about 5 minutes or less after implantation of the implantablemedical device. More preferably, such time period is about 3 minutes orless, even more preferably about 2 minutes or less, and most preferablyabout 1 minute or less, e.g. in the range of about 20 seconds to about 1minute. Such embodiments configured for relatively rapid delivery areespecially beneficial when the releasable component is carried by asurface of a temporarily implantable medical device structure, forexample a balloon of a balloon catheter, including any balloon catheterand in any coating arrangement described herein.

In other embodiments, the excipient increases the durability of thecoating to resist the undesirable premature release of the drug from adevice prior to delivery to a point of treatment within a body vessel.For example, the excipient can decrease the amount of drug releasedprematurely during folding and unfolding of a balloon portion of aballoon catheter or during crimping of an expandable stent. Likewise,the excipient may decrease the amount of drug loss during delivery of amedical device, such as a balloon or stent, to the treatment site.

In certain embodiments, coated stents disclosed herein exhibit a drugamount loss of less than about 10%, more preferably less than about 8%,6%, 4%, 3%, 2%, 1% or 0.5% and most preferably less than about 0.1% uponcrimping to a diameter of 6 French (6 F) and expansion. In otherembodiments, coated balloons disclosed herein exhibit a drug amount lossof less than about 10%, more preferably less than about 8%, 6%, 4%, 3%,2%, 1% or 0.5% and most preferably less than about 0.1% during foldingand unfolding of the balloon.

In those embodiments in which the releasable component is contained as acoating layer, any of a wide variety of coating patterns may be used toconstitute a material coat on the medical device. The coating layer canbe directly adhered to a surface of an implantable structure of themedical device and provide an outermost surface over the implantablestructure, and/or to constitute the entirety of the overall materialcoat on the implantable structure. In other embodiments, an overallmaterial coat adhered to the implantable structure of the medical devicecan include one or more different coatings positioned underneath thelayer including the releasable component (e.g. as in a polymeric orother primer coating, or a different drug coating, adhered directly tothe surface of the medical device), one or more different coatingspositioned overtop the layer including the releasable component (e.g. asin a polymeric or other protective or diffusion barrier coating), orboth. As well, there may be one or more different coatings adjacent thelayer including the releasable component, and/or multiple layersincluding the releasable component may be carried by the implantablemedical device at locations discrete from one another. The layerincluding the releasable component may be present in an aperture(s) suchas a well(s), groove(s) or hole(s) defined in the implantable medicaldevice (e.g. in a stent) or may partially coat or completely coat theimplantable medical device or a given surface (e.g. inner, outer or sidesurface) of the implantable medical device. These and other overalldevice coating arrangements can be utilized.

The layer including the releasable component can be carried by anysuitable surface of the implantable medical device structure. The layerincluding the releasable component can be carried by, and in someembodiments only by, a surface or surfaces of the implantable medicaldevice configured for contact with patient tissue when the device isimplanted. For example, in some embodiments the layer including thereleasable component is carried by a surface of a balloon of a ballooncatheter, or by a surface of a stent, which is configured for contactwith a wall of a vessel when the balloon is implanted (usuallytemporarily) or when the stent is implanted (usually permanently). Inparticular embodiments, in the case of a balloon of a balloon catheterwhich inflates to provide a substantially cylindrical outer surface asdiscussed above, the layer including the releasable component is carriedby such substantially cylindrical outer surface, either partially orcompletely covering the substantially cylindrical surface. In the caseof a stent having an outer surface as discussed above, the layerincluding the releasable component can be carried by the outer surface,either partially or completely covering the outer surface.

The layer including the releasable component and any other coatinglayers present can be incorporated as a part of the implantable medicaldevice by any suitable method. This layer and any other coating layercan be formed on a surface of the implantable medical device. Forexample, the layer or other coating layer(s) can be formed by a methodthat includes dipping, spraying, showering, dripping, or otherwiseapplying a medium containing the coating ingredients, and optionally asubstance such as a solvent can be removed from the medium to leave thecoating adhered to the implantable medical device. Spray coating is onepreferred form of applying the coating materials to the surface of theimplantable medical device, and in particular embodiments ultrasonicspray coating will be utilized. During spray coating or other coatingoperations, the implantable medical device can be moved relative to asprayer or other applicator of the coating ingredients. This can occurby moving the implantable medical device (including for example rotatingthe device or at least the portion to be coated), moving the sprayer orother applicator, or both. Multiple application passes or steps willtypically be utilized to increase the thickness of the layer includingthe releasable component or other coating layer(s) and control thelevels of the drug, excipient, or other ingredients applied to theimplantable medical device. In spray or other application processes,areas of the implantable medical device adjacent to areas desired forcoating can optionally be masked to prevent the application of coatingmaterials to the masked areas, and/or portions of applied coatingmaterials can be removed to selectively leave a layer including thereleasable component or other coating in a desired region or regions ofthe device.

The layer including the releasable component can be constituted entirelyof the drug and excipient, or may, for example, include a biostablepolymer, where the polymer remains attached to the device structure asreleasable component released. Alternatively, or in addition to thebiostable polymer, this layer may include a bioabsorbable polymer. Sucha polymer layer can include a polymeric matrix, e.g. made using asuitable polymer as identified herein, and in certain forms will be aporous layer that releasably contains an admixture including the drugand excipient in the pores thereof.

In certain embodiments, the releasable component is contained within thestructure of the implantable device. For example, in those devicesincluding a polymer component, the releasable component may be includedin the mixture inserted in a mold to form at least part of the structureof the device. In certain embodiments, a mixture including thereleasable component and a polymer is extruded to form at least part ofthe structure of the device. In other embodiments, the releasablecomponent is imbibed into pores of a polymeric component of the deviceafter this component is formed.

In certain aspects, a coated medical device as described herein,preferably comprising a stent and/or balloon catheter carrying thereleasable component, can be configured to, and used to, treat anysuitable body passage in a manner including release of the drug to thewall tissue of the body passage. The body passage may for example be avein, artery, biliary duct, ureteral vessel, body passage or portion ofthe alimentary canal. A coated medical device as described herein may beused to treat a coronary artery, carotid artery, or a peripheral arteryor vein, including as examples a renal artery or vein, iliac artery orvein, femoral artery or vein, popliteal artery or vein, subclavianartery or vein, intercranial artery or vein, aorta, vena cava, orothers. In preferred embodiments, the coated medical devices will treator prevent stenosis or restenosis in a body passage such as any of thoseidentified herein, although treatment of other conditions iscontemplated for other embodiments of the invention. In certainembodiments, the coated medical device is configured to, and used to,treat a narrowing of a peripheral artery or vein. Examples of sucharteries include, but are not limited to, the femoral artery, thesuperficial femoral artery (artery below the branch for the profundafemoris artery), the popliteal artery and the infrapopliteal artery.Examples of such veins include, but are not limited to, the common iliacvein, external iliac vein, femoral vein, the popliteal vein and thelesser/greater saphenous vein.

With reference now to FIGS. 1-5, shown is one embodiment of adrug-delivering balloon catheter 20 in accordance with the embodimentsof the invention. Balloon catheter 20 includes a catheter shaft 22 and aballoon 24 mounted thereon. A material coat 26 including a layercontaining a drug and excipient 26 a as described herein is carried byballoon 24. Catheter shaft 22 includes a first lumen 28 and second lumen30. Lumen 28 is configured for inflation of balloon 24, and lumen 30 isconfigured to receive a guide wire 32 or other guide member to be usedin conjunction with balloon catheter 20. Balloon 24 includes an interiorregion 34 designed to receive a liquid or other fluid for inflation ofballoon 24. Balloon 24 has an inner wall 36 bounding balloon interior34, and an outer wall surface 38. Layer 26 is adhered to outer wallsurface 38 of balloon 24.

Balloon catheter 20 also includes a catheter hub 40 mounted to shaft 22.Catheter hub 40 defines a first opening 42 which fluidly communicateswith balloon inflation lumen 28, and a second opening 44 which fluidlycommunicates with lumen 30 defined by shaft 22. Opening 42 of hub 40 andlumen 28 communicate with an opening 46 into the interior 34 of balloon24, for passage of the inflation fluid for the balloon 24. Opening 44 ofhub 40 and lumen 30 defined by a catheter shaft 22 extend to distalopening 48 of lumen 30, with distal opening 48 positioned distally ofballoon 24.

With reference to FIG. 5 still in conjunction with features shown inFIGS. 1-4, balloon 24 includes a balloon wall 50, for example defined bya conventional balloon film, typically made from a polymeric materialsuch as one of those discussed hereinabove. Balloon wall 50 as shown inFIGS. 4 and 5 is in a folded condition, useful during insertion ofballoon 24 into a vessel such as an artery or vein. In its foldedcondition, balloon 24 includes pleats 52, 54, 56, 58, and 60. As shown,pleats 52-60 are arranged in a spiral pattern with each pleat in acurved condition extending circumferentially around the portion ofcatheter shaft 22 over which they occur, with the pleats overlapping andthereby contacting one another along at least a portion of their length.In this folded arrangement, pleats 52, 54, 56, 58, and 60 includeexternally-exposed pleat surfaces 52 a, 54 a, 56 a, 58 a, and 60 a, andinternal non-exposed pleat surfaces 52 b, 54 b, 56 b, 58 b, and 60 b.Correspondingly, material coat 26, which in the illustrated embodimentincludes coating layer 26 a, has externally-exposed portions positionedon externally-exposed pleat surfaces 52 a-60 a, and internal non-exposedportions positioned on internal non-exposed pleat surfaces 52 b-60 b.Also in this arrangement, because pleats 52-60 overlap with one another,regions of material coat 26 and its drug and excipient 26 a are incontact with other regions of material coat 26 and its drug andexcipient 26 a. In reference to FIG. 5, it should be understood that thefeatures shown therein are intended to be illustrative, and that inpractice balloon 24 is typically tightly pleated and wrapped aroundcatheter shaft 22 and thus there will often be little or no open spaceon the interior of pleats 52-60.

Referring now to FIG. 6, shown is another embodiment of a ballooncatheter having features similar to those of balloon catheter 20 ofFIGS. 1-5, but wherein material coat 26 includes a first coating layer26 a, which is a layer containing drug and excipient as describedherein, and a second coating layer 26 b different from this layer andpositioned underneath coating layer 26 a. Coating layer 26 b may, incertain embodiments, be a polymeric primer layer as discussed above.

Referring to FIG. 7, shown is another embodiment of a balloon cathetersimilar to balloon catheter 20 of FIGS. 1-5, except wherein materialcoat 26 includes a first coating layer 26 a, which is a layer containingdrug and excipient as described herein, adhered directly to the outersurface 38 of balloon 24, and a second coating layer 26 b positionedovertop coating layer 26 a. Coating layer 26 b of FIG. 7 may, in certainembodiments, be a polymeric protective layer and/or a polymericdiffusion barrier layer operable to control the release of the drugthrough the diffusion barrier layer.

FIGS. 5a and 5b show balloon catheter embodiments similar to that shownin FIGS. 1-5 except having a different coating pattern for material coat26. In particular, in FIG. 5a , the material coat 26 including the layercontaining drug and excipient 26 a is carried only by the externallyexposed surfaces 52 a-60 a of pleats 52-60. This configuration may beprepared, for example, by coating selected surface areas of the balloon24 while in the inflated condition that will upon folding be positionedas externally exposed pleat surfaces 52 a-60 a, or by coating balloon 24while in the folded condition under folding and coating conditions thatcoat only the externally exposed pleat surfaces 52 a-60 a. FIG. 5bdiscloses a balloon catheter embodiment in which the material coat 26 iscarried only by internal non-exposed pleat surfaces 52 b-60 b. Thisconfiguration may be prepared, for example, by coating selected surfaceareas of the balloon 24 while in the inflated condition that will uponfolding be positioned as internal non-exposed pleat surfaces 52 b-60 b,or by coating balloon 24 completely circumferentially while in theinflated condition, pleating and folding the balloon, and then removingthe material coat 26 portions on the externally exposed pleat surfaces52 a-60 a, for example mechanically and/or with a solvent or othermedium capable of displacing the material coat 26. Layer 26 a of theembodiments of FIGS. 5a and 5b can be applied in any suitable fashion,including using any of those methods described herein. As well, thematerial coat 26 of the embodiments of FIGS. 5a and 5b can, in otherembodiments, be a multi-layer coating such as those shown and describedherein, including those shown and described in conjunction with FIGS. 6and 7.

FIG. 8 illustrates another embodiment of the invention. A stent 70includes a stent body 72 defining a central lumen 74. Stent body 72includes a plurality of longitudinally-adjacent segments 76 includingstruts defining a circumferential path about lumen 74 and a pattern ofconnecting strut segments 78 connecting adjacent segments 76. A coating86 (see exploded section, lower right) including a layer containing drugand excipient 86 a is carried by a surface of stent 70. In theillustrated embodiment, the layer 86 a is adhered directly on thesurface of stent 72 as the sole coating, although in other embodimentsthe stent coating 86 may be a multi-layer coating such as those shownand described herein, including those coatings shown and described inconjunction with FIGS. 6 and 7. Stent 72 has outer strut surfaces 80configured for contact with a vessel wall such as an artery or vein wallof a patient. Stent 72 has an inner strut surface 82 opposite the outersurfaces 80 and generally facing the lumen 74. Stent 72 also has strutsidewall surfaces 84 between outer and inner strut surfaces 80 and 82.Strut outer surfaces 80 carry the material coat 86 over at least aportion of the outer surface of stent 72 and in certain embodiments overthe entire or essentially the entire outer surface of stent 72. Stent 72is desirably a self-expanding stent and is preferably made of aresilient metal, preferably a superelastic metal alloy such as asuperelastic nickel-titanium (Ni—Ti) alloy, as occurs for example in theZILVER® nitinol stent commercially available from Cook Medical,Bloomington, Ind., USA. Stent 72 can be manufactured using methods andmaterials disclosed herein for stents or otherwise, and the layer 86 aand any other coating(s) present on the stent may have any compositiontaught herein and may be incorporated onto stent 72 in any suitablefashion, including any of those disclosed herein.

FIG. 9 illustrates another embodiment of the invention. The implantablemedical device 20′ of FIG. 9 is similar to that shown in FIG. 4, exceptalso having a balloon-expandable stent 90 mounted over balloon 24. Stent90 has a proximal end 92 and a distal end 94. In this or other ballooncatheters having a stent mounted on the balloon, either stent 90,balloon 24, or both, can carry a layer containing drug and excipient ona surface thereof. In the illustrated embodiment 20′, the stent 90 has amaterial coat 96 including a layer containing drug and excipient 96 acarried by an external surface thereof, and the balloon 24 has amaterial coat 26 including a layer containing drug and excipient 26 acarried by the surface of balloon 24. The coating layer 26 a can becarried on the balloon 24 so as to extend proximally of proximal end 92of stent 90 and distally of distal end 94 of stent 90. In this fashion,the drug(s) of the layer containing drug and excipient, when balloon 24is inflated in a vessel such as an artery or vein to dilate the vesseland implant the stent 90, can be applied to the vessel in regionsextending proximally and distally of the stent 90. Where the drug(s) isor includes a restenosis-inhibiting agent, this can inhibit restenosisthat may otherwise occur due to edge effects experienced at or near theproximal 92 and distal 94 ends of the stent 90.

The balloon and other components of the balloon catheter of device 20′,and the stent 90, can be manufactured using methods and materialsdisclosed herein for the same or otherwise. The material coat 26 and/ormaterial coat 96 can include a sole layer 26 a or 96 a adhered directlyto the surface of balloon 24 or stent 90, respectively, although inother embodiments the balloon material coat 26 or stent material coat 96may be a multi-layer coating such as those shown and described herein,including those coatings shown and described in conjunction with FIGS. 6and 7. The layer containing drug and excipient and any other coatinglayer(s) present on the balloon and/or stent of device 20′ may have anycomposition taught herein and may be incorporated onto the balloon 24and/or stent 90 in any suitable fashion, including any of thosedisclosed herein.

FIGS. 10 and 11 depict another embodiment of the invention. FIG. 10provides a side view of a drug-delivering scoring balloon according toone embodiment. FIG. 11 provides an enlarged cross-sectional view of aportion of the balloon of FIG. 10 including a dilatation element. Morespecifically, a drug-delivering scoring balloon catheter 100 includes acatheter shaft 102 and a balloon 104 mounted thereon. Balloon 104 hasattached thereto, and preferably integrally formed with a balloon wallfilm 106 thereof, a plurality of dilation elements 108 projectingoutwardly with respect to the balloon wall film 106 that spans betweendilation elements 108. A material coat 110 including a layer containingdrug and excipient 110 a as described herein is carried by balloon 104and in the specific illustrated embodiment by both the balloon wall film106 and the dilation elements 108. Dilation elements 108 as depicted aretrizoid-shaped elements; however, other shapes will be suitable for usein embodiments of the present invention, and dilation elements can beprovided by separately attached or embedded articles or materialsinstead of being integrally formed with the balloon wall film. Cathetershaft 102 includes a first lumen 112 and second lumen 114. Lumen 112 isconfigured for inflation of balloon 104, and lumen 114 is configured toreceive a guide wire or other guide member to be used in conjunctionwith balloon catheter 100. In the embodiment depicted, the layercontaining drug and excipient 110 a is directly adhered to outer wallsurface of balloon 104 and in particular the outer surface of balloonwall film 106 and dilation elements 108. It will be understood that inother embodiments, this layer can be a part of a material coat thatincludes multiple layers, including any of those multiple layer coatingsdescribed hereinabove, and thus can have other coating layers underneathor overtop the layer containing drug and excipient. In addition oralternatively, the layer containing drug and excipient or material coatincorporating it can extend completely circumferentially around theballoon 104, coating both the dilation elements 108 and the balloon wallfilm 106 spanning between the dilation elements 108 (as in FIGS. 10 and11), or selective portions of the balloon 104 can be coated.Illustratively, the dilation elements 108 can be completely or partiallycoated with the layer containing drug and excipient or other materialcoat including it while the balloon wall film 106 spanning between thedilation elements 108 can be uncoated or at least free of the layercontaining drug and excipient or other material coat including it; or,the balloon wall film 106 spanning between the dilation elements 108 canbe completely or partially coated with the layer containing drug andexcipient or other material coat including it while the dilationelements 108 can be uncoated or at least free of the layer containingdrug and excipient or other material coat including it. These and othercoating arrangements will be suitable herein. As well, while the balloon104 is shown in its expanded condition, it will be understood thatembodiments herein will include balloon 104 in a folded condition,including for example any of those folded conditions, and structuralfeatures provided thereby, described hereinabove.

The following examples illustrate the present invention. The examplesand embodiments described herein are for illustrative purposes only andmodifications or changes in light thereof will be suggested to oneskilled in the art without departing from the scope of the presentinvention.

EXAMPLE 1 Coating of Paclitaxel and Additive onto the Surface of aBalloon Catheter

Paclitaxel and tannic acid are coated onto a balloon catheter at a ratioof 1:2 paclitaxel to tannic acid. The final goal dose coated onto theballoon is approximately 1,300 micrograms per balloon, or about 1.5micrograms/mm².

A working stock solution for balloon catheter coating is prepared. 66.6mg of paclitaxel and 133.33 mg of tannic acid are weighed in a 22 mLglass vial. 10 mL of EtOH is transferred into the vial containing thedrug and additive, which is then sonicated until the solution ishomogenous. Typically, the mixture is sonicated for approximately 10minutes.

A balloon (Cook Advance 18LP 7 mm×40 mm, Cook Medical Incorporated) isheld horizontally within an apparatus capable of rotating the balloonalong its longitudinal axis. The balloon is inflated so that it iscompletely expanded and the motor is turned on to begin rotation of theballoon. Using a 100 microL pipette, 65 microL of the above workingsolution is measured. Holding the pipette on the most proximal surfaceof the balloon the solution is slowly released from the pipette onto theballoon. During coating, the pipette tip is slowly dragged along thesurface of the balloon while constantly releasing the solution. Care istaken to avoid gaps or overlaps of the coating. The first 65 microL iscoated on the proximal ⅓rd of the balloon. The central and distal ⅓rdportions of the balloon were coated in the same manner.

The above steps are repeated twice to coat the remainder of the ballooncatheter. A small volume drip of EtOH can be used after the initial drugcoating to even out the coating and rinse the solution vial and pipettetip to ensure that all of the drug was coated onto the balloon. Afterthe entire volume of solution is coated onto the surface, the ethanol isallowed to evaporate for up to 5 minutes, at which time the coatingcrystalizes and turns white. After the balloon has dried it is deflated,removed for the rotating apparatus, folded, and covered.

A similar balloon is inflated and coated using a spray coating method.Briefly, the stock solution is sprayed onto the surface of the inflatedballoon using a stray gun and the solvent (for example, ethanol) allowedto evaporate. After the balloon has dried it is deflated, removed forthe rotating apparatus, folded, and covered.

EXAMPLE 2 Tissue Uptake Study

Flow loop testing is conducted to test the uptake of drug from a coatedballoon into external porcine iliacs. The flow loop set up is asfollows. The excess fat and tissue is removed from external porcineiliacs, which are cut to approximately 6 cm in length. The externaliliacs are stored overnight in a refrigerator for testing the followingday.

A flow loop testing circuit is set up as follows. Briefly, a porcineiliac is removed from the refrigerator and weighed. Black neoprenetubing is cut to the length needed to connect the inflow end of theporcine iliac to a reservoir containing approximately 150 mL ofphosphate buffered saline (PBS) at 37C. A three-way connector is presentin the tubing to allow a balloon catheter to be inserted through thetubing and into the porcine iliac.

The outflow end of the porcine iliac is connected by neoprene tubing toform a return path to the reservoir. For example, the PBS can becontained in a 250 ml Buchner flask. This results in a completed loopfor circulation of PBS. Any side branches of the porcine iliac aresealed off before it is immersed in a tissue bath containingapproximately 1500 mL of 9% saline at 37C.

A peristaltic pump is set to cycle the PBS at 480 ml/min and turned onto test that the PBS has a smooth flow and there is no leaking anywherein the loop, especially in the tissue. To begin testing, a dilator andflexor sheath are inserted through the 3 way connector and to the siteof inflation in the porcine iliac. The dilator is retracted. Aninflation device is filed with approximately 20 mL of tap water andconnected to the inflation lumen of a balloon coated using the procedureof Example 1. The balloon is degassed, fed into the sheath and trackedto the end in 40 seconds. This time is chosen to simulate the timetypically taken for the balloon to reach the treatment site in vivo.After 40 seconds, the flexor is drawn back to expose the balloon to thetissue. After 20 seconds (60 seconds total), the balloon is inflated to8 atm with the inflation device. The peristaltic pump is then turnedoff.

While maintaining 8 atm for 5 min, vials are prepared with 10 mL of EtOHfor the balloon and tissue dosing. After 5 min at 8 atm, the balloon isremoved from the flexor. The balloon is cut off the catheter into a vialwith EtOH.

The peristaltic pump is turned on and the flow monitored for 1 min,allowing any particulate that isn't stuck in the tissue to wash away.After 1 min, the pump is turned off and the porcine iliac removed. Theiliac is cut into 2 cm sections, which are placed into the preparedvials. 1 mL of the circulating PBS solution is pipetted into an HPLCvial. After the testing is completed, the vials are placed on a shakingincubator at 37° for 4 hours and then filtered through a 0.45 micronPVDF filter. All samples (balloon, PBS, and tissue) are run on the HPLCafter the tissue extraction is finished.

FIG. 12 shows flow loop results obtained using the above protocol.Balloons are coated with a mixture of paclitaxel and tannic acid using aprotocol similar to that described in Example 1. The ratio of paclitaxelto tannic acid is either 1:2 or 1:3. The coatings are performed usingeither a drip coating (1:2 #1D) or spray coating (1:3, 1:2#1S, 1:2#2S).The tissue uptake of drug is shown as a percentage of the initial drugon the balloon. The percentage uptake obtained using a commerciallyavailable drug coated balloon (“OTM DCB”) is shown for comparison.

EXAMPLE 3 Durability Testing Study

Durability testing is conducted to test the amount of drug loss from theballoon catheter during different phases of balloon delivery anddeployment. Drug loss during folding, delivery to the site of inflation,and upon inflation is tested. To test for drug loss from folding, theballoon is coated and naturally deflated to recreate the folds, a vacuumis pulled, and a balloon cover is positioned over the balloon. Coatingis performed using either a drip or spray coating method following thegeneral protocol described in Example 1. After approximately 24 hours,the balloon cover is removed and the balloon is inflated. The balloon isthen placed in a container and rinsed with 100% ethanol. The amount ofdrug remaining on the balloon is quantified on HPLC.

To test for drug loss during delivery of a balloon to the treatmentsite, the flow loop is set up as in Example 2 except that the pig vesselis replaced by a silicone tube. The PBS bath is not used in thisexperiment. The fluid flow is turned on and balloon is then tracked tothe end of the silicone tube, without extending out of the tubing. Thisprocess is performed over a period equivalent to the tracking time of aballoon in vivo (about 40 seconds). After the appropriate period of timehas passed the flow loop is shut off and the balloon is pushed out ofthe tubing and exposed to the air. At this time the end of the ballooncatheter is cut off and the balloon is placed in a vial of 100% ethanolfor drug quantification on HPLC.

To test for the drug loss during inflation of the balloon, the same setup as is used to test for drug loss during delivery it utilized. Afterapproximately 40 seconds the balloon is inflated within the siliconetubing and the flow is shut off. The balloon is deflated after a verybrief period of time, pushed out the end of the silicone tubing and theballoon is cut off and placed in a vial of 100% ethanol for drugquantification on HPLC.

FIG. 13 shows the effect of tannic acid (TA) or EGCG on the durabilityof the drip (#D) or spray (#S) coating. The durability is better at a1:2 (paclitaxel: tannic acid or EGCG) ratio, with less drug loss duringballoon delivery and inflation in comparison to coatings at either 1:25or 1:100 (paclitaxel:tannic acid.)

Although the invention has been described and illustrated with referenceto specific illustrative embodiments thereof, it is not intended thatthe invention be limited to those illustrative embodiments. Thoseskilled in the art will recognize that variations and modifications canbe made without departing from the true scope and spirit of theinvention as defined by the claims that follow. It is therefore intendedto include within the invention all such variations and modifications asfall within the scope of the appended claims and equivalents thereof.

I claim:
 1. A medical device comprising: a base structure having asurface, and a coating on the surface comprising a drug and anexcipient, wherein the drug and excipient are present at a weight ratioof between 10 to 1 and 1 to 10 drug to excipient, and wherein theexcipient is selected from the group consisting of a gallate containingcompound, epi gallo catechin gallate, tannic acid and epi catechingallate.
 2. The medical device of claim 1, wherein the drug is arestenosis-inhibiting agent.
 3. The medical device of claim 1, whereinthe excipient is selected from a group consisting of epi gallo catechingallate and tannic acid and epi catechin gallate.
 4. The medical deviceof claim 3, wherein the excipient is tannic acid.
 5. The medical deviceof claim 3, wherein the excipient is epi gallo catechin gallate.
 6. Themedical device of claim 1, wherein the coating consists essentially ofthe excipient and the drug.
 7. The medical device of claim 1, whereinthe drug is selected from the group consisting of an immunosuppressiveagent, an antiproliferative agent, a microtubule stabilizing agent, arestenosis-inhibiting agent, a smooth muscle cell inhibitor and aninhibitor of the mammalian target of rapamycin.
 8. The medical device ofclaim 1, wherein the drug is selected from the group consisting ofsirolimus, pimecrolimus, tacrolimus, everolimus, zotarolimus, novolimus,myolimus, temsirolimus, deforolimus and biolimus.
 9. The medical deviceof claim 1, wherein the drug is paclitaxel.
 10. The medical device ofclaim 9, wherein the paclitaxel is selected from the group consisting ofamorphous paclitaxel, dihydrate paclitaxel, anhydrous crystallinepaclitaxel and a mixture of at least two thereof.
 11. The medical deviceof claim 9, wherein the paclitaxel is present in an amorphous and acrystalline form.
 12. The medical device of claim 1, wherein the coatingis free of a polymer or non-polymer carrier matrix.
 13. The medicaldevice of claim 1, wherein the coating comprises less than 1 percentageby weight of a polymer or non-polymer carrier matrix
 14. The medicaldevice of claim 1, wherein the medical device is a balloon.
 15. Themedical device of claim 1, wherein the medical device is a stent. 16.The medical device of claim 1, wherein the medical device is selectedfrom the group consisting of a stent, a vascular stent, a ureteralstent, a catheter, a balloon, a balloon catheter, a stent graft, a wireguide, and a cannula.
 17. The medical device of claim 1, wherein thedrug is present in more than one polymorphic form.
 18. The medicaldevice of claim 1, wherein the excipient is present in an amounteffective to increase a rate of release of the drug from the medicaldevice when implanted in a patient.
 19. The medical device of claim 1,wherein the drug is a water-insoluble drug.
 20. A medical devicecomprising: a balloon having an outside surface, and a coating on theoutside surface, the coating comprising paclitaxel and an excipient,wherein the paclitaxel and excipient are present at a weight ratio ofbetween 10 to 1 and 1 to 10 paclitaxel to excipient, wherein thepaclitaxel is present in an amorphous and a crystalline form, andwherein the excipient is selected from the group consisting of a epigallo catechin gallate and tannic acid.